Apoptosis is a morphologically distinct from of programmed cell death that plays important roles in development, tissue homeostasis and a wide variety of diseases, including cancer, AIDS, stroke, myopathies and various neurodegenerative disorders. Mitochondria have a key function for; sensing and propagating cell death signals. For example, the release of cytochrome c from mitochondria into the cytoplasm is thought to be a critical step for activating the cell death program. A new mitochondrial protein, termed-ARTS (Apoptosis Related protein in the TGF-beta Signaling pathway), appears to mediate the induction of apoptosis in mammalian cells in response to several distinct death-inducing stimuli. ARTS is a novel septin protein family member that translocates; from mitochondria to the nucleus at the onset of apoptosis. Furthermore, a Drosophila homolog of ARTS, encoded by the peanut locus, is required for the induction of cell death by the pro-apoptotic genes reaper, hid and grim in this organism. The overall objective of the proposed research is to use an integrated approach that combines Drosophila genetics and molecular biology with mammalian cell culture experiments to gain insight into the mechanism by which ARTS induces apoptosis. We will address the following specific questions: 1. How conserved is the pro-apoptotic function of human ARTS and Drosophila PEANUT? 2. What is the role of ARTS for cell killing by the pro-apoptotic proteins Reaper, Hid and Grim in mammalian cells? 3. Where in the cell does ARTS act to induce apoptosis? 4. Are there functional and biochemical interactions between ARTS/peanut with IAPS (inhibitor of apoptosis proteins) and Sina/Siah proteins? This work should significantly advance our understanding of how apoptosis is regulated, and how this process can be manipulated for therapeutic purposes.